Delayed Toxicity From Systemic Therapy
Delayed toxicity from systemic therapy for germ cell tumors has been well characterized. In the absence of signs and symptoms, specific monitoring for these late effects is not generally warranted. A number of late effects have been observed.
Fertility problems and fetal malformation
Fertility problems, manifested by azoospermia or oligospermia at or beyond 2 years, occur in 45% to 55% of treated patients. No increased risk of fetal malformation has been observed in the offspring of men previously treated with chemotherapy for testicular cancer.
Several reports have documented an increase in prevalence of cardiovascular risk factors and cardiovascular disease in patients with a history of testicular germ cell tumors who were treated with chemotherapy or radiotherapy (even infra-diaphragmatic is associated with increased risk of cardiovascular disease). Haugnes et al reported on cardiovascular risk factors and morbidity in survivors of testicular cancer. Median follow-up was 19 years. Treatment with chemotherapy was associated with increased prevalence of antihypertensive medication use. Radiation therapy was associated with a higher prevalence of diabetes. Cardiovascular disease was increased in patients who received chemotherapy or radiotherapy and especially in patients who received both modalities. Raynaud phenomenon also occurs at a rate directly proportional to the number of cycles of cisplatin(Drug information on cisplatin)-based chemotherapy.
Renal and pulmonary toxicities
Although renal and pulmonary dysfunction can occur acutely during therapy, long-term consequences from therapy are uncommon. Of special note is the concern about bleomycin(Drug information on bleomycin)-related pulmonary toxicity. Overall risk is associated with cumulative doses of bleomycin; this was found in 8.5% of patients who received more than 300 units. Pulmonary toxicity may manifest as bronchiolitis obliterans with organizing pneumonia, eosinophilic hypersensitivity, or interstitial pneumonia.
Perhaps of greatest concern is the development of late recurrences or secondary malignancies.
The incidence of late recurrence is estimated at 3.2% in NSGCT and 1.4% in seminoma. These late recurrences typically occur beyond 5 years (longest, 32+ years) from primary therapy, frequently present with an elevated serum level of AFP, and are particularly resistant to salvage chemotherapy. Thus, surgical resection of disease is the primary treatment strategy. Sharp et al reported on 75 patients with late recurrence, noting that the 5-year cancer-specific survival (CSS) was 79% vs 36% for men who underwent complete or incomplete surgical resection, respectively. The 5-year CSS for chemotherapy-naive patients was 93% compared with 49% for men who had a history of chemotherapy in their initial management.
Approximately 1% to 2% of patients may develop a second primary testicular cancer. As such, several examinations should be part of every physical examination.
In a large series of 40,000 men reported by Travis et al, the relative risk for developing secondary tumors was 1.9 for 10-year survivors of testicular cancer, and it remained 1.7 for 35-year survivors. The greatest elevated risk was for cancers of the pleura, pancreas, bladder, and stomach. In another large retrospective analysis of 635 patients with extragonadal germ cell tumors treated from 1975 to 1996, only an increased number of hematologic and skin malignancies were observed.
The contribution of chemotherapy and/or radiation therapy to the development of these other malignancies, as opposed to a natural propensity toward their development, is unknown. Theoretically, radiation exposure during follow-up CT scans might contribute to the increased risk of cancer.
Etoposide has been shown to pose an increased risk for the development of secondary leukemia (dose-related). At higher dosages (> 2 g/m2 cumulative), etoposide(Drug information on etoposide) has been associated with a greater incidence of acute leukemia (associated with 11q23 chromosomal abnormality). Very high dosages of etoposide with stem cell rescue do not appear to be linked to a higher risk than standard-dose chemotherapy. In one article by Travis et al, both increased dosages of radiation therapy and cisplatin were associated with an increased risk for acute leukemia. Although these risks are real, they still are low compared with the risk of death caused by testicular cancer. Nonetheless, indiscriminate use of chemotherapy for early-stage (stage I) disease should be tempered by the recognition of the long-term hazards of therapy. Currently, there are no data to suggest that additional screening beyond standard guidelines for the general population is beneficial.
Follow-Up for Relapse
Because the relapse rate for testicular cancer is low, patients with pathologically confirmed stage I NSGCTs require no further therapy, and follow-up can be accomplished easily with chest radiography, tumor markers, and physical examination. Similarly, for patients who have stage II disease and receive adjuvant chemotherapy, the risk of relapse is low. For patients with either of these two clinical scenarios, follow-up tests (chest radiography, serum markers) should be performed every 2 months for 1 year, every 4 months for the second year, every 6 months for years 3 through 5, and annually thereafter.
In patients with resected stage II NSGCTs who do not receive adjuvant chemotherapy, the follow-up tests are the same as those listed above. However, in these patients, follow-up tests are performed every month for 1 year, every 2 months for 2 years, every 6 months for years 3 through 5, and then annually.
Sidebar: Walraven et al retrospectively reviewed data sets of 2,569 patients treated for testicular cancer between 1991 and 2004. After a median of 10 CT scans and 11.2 years of follow-up, non–germ cell malignancy was diagnosed in 14 patients (5 per 10,000 patient-years). The risk of cancer was not associated with the amount of diagnostic radiation exposure. (Walraven et al: J Clin Oncol 29:2883-2888, 2011).